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Targeting complement to enhance antitumor immunity and control malignant effusions in patients with recurrent epithelial ovarian cancer

Award Number: R01CA267690
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting complement to enhance antitumor immunity and control malignant effusions in patients with recurrent epithelial ovarian cancer - Abstract Epithelial ovarian cancer (OC) is the leading cause of death from gynecological malignancies in the United States. While OC is immunogenic and increased infiltration of cytotoxic T lymphocytes (CTL) correlates with longer survival, single agent checkpoint inhibitors are largely ineffective in the relapsed/refractory setting. Our long-term goal is to develop novel approaches to overcome obstacles to durable antitumor immunity to make immunotherapy more effective. Our results point to previously unrecognized mechanisms for mature neutrophils acquiring a suppressor phenotype within the tumor microenvironment (TME). Neutrophil suppressors inhibited stimulated proliferation of circulating naïve, central memory, and effector memory T cells, and of tumor-associated lymphocytes (TAL) from patients with newly diagnosed OC. Induction of the neutrophil suppressor phenotype required complement signaling and NADPH oxidase activation. A similar complement- dependent neutrophil suppressor phenotype was induced by ascites from patients with recurrent OC and from malignant effusions from patients with a number of metastatic cancers, underscoring the generalizability of our findings. These results in human samples and work by others in tumor-bearing mice support targeting complement to enhance anti-tumor immunity. We will evaluate APL-2, a peptide C3 inhibitor, in a randomized phase 2 clinical trial in patients with recurrent OC and persistent malignant effusions. APL-2 was safe and superior to eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) and is FDA-approved for this indication; it’s use in cancer is novel. Following a safety lead-in, patients will be randomized to the following cohorts: (i) bevacizumab (anti-VEGF); (ii) APL-2 + pembrolizumab (anti-PD1); and (iii) APL-2 + pembrolizumab + bevacizumab. Specific Aim 1: To evaluate safety and control of malignant effusions as primary endpoints and progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and quality of life (QoL) as secondary endpoints. Specific Aim 2: To determine the effects of APL-2-based therapy in modulation of immune responses in the TME. Patient samples (blood, effusion, tumor) will be collected at baseline and at pre-specified time points during the trial. We will test the extent that APL-2 will abrogate neutrophil suppressor activity and expand activated T cells in the TME. A combination of functional studies and transcriptional and mass cytometry profiling of circulating and ascites neutrophils and T cells will be performed. The impact of our proposal is to gain safety and preliminary efficacy data on APL-2- based regimens in recurrent OC with malignant effusions and a detailed understanding of how these regimens modulate the immune landscape in the TME. This research is expected to establish the foundation for larger randomized trials to definitively test the efficacy of C3 inhibition in enhancing cancer immunotherapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $618,854 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	3	7/19/2024	NON-COMPETING CONTINUATION	$618,854
														Subtotal = $618,854

Issue Date FY: 2023 ( Subtotal = $645,738 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	000	2	7/24/2023	NON-COMPETING CONTINUATION	$645,738
														Subtotal = $645,738

Issue Date FY: 2022 ( Subtotal = $693,903 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	000	1	8/24/2022	NEW	$693,903
														Subtotal = $693,903

Grand Total All Awards = $1,958,495

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Targeting complement to enhance antitumor immunity and control malignant effusions in patients with recurrent epithelial ovarian cancer

Award Number: R01CA267690

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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